title: The ubiquitin-specific protease USP34 regulates axin stability and Wnt/β-catenin signaling.
abstract: Wnt proteins control multiple cell behaviors during development and tissue homeostasis. However, pathological activation of Wnt signaling is the underlying cause of various human diseases. The ubiquitin-proteasome system plays important regulatory functions within the Wnt pathway by regulating the activity of several of its core components. Hence, multiple E3 ubiquitin ligases have been implicated in its regulation. Less is known, however, about the role of ubiquitin-specific proteases in Wnt signaling. Analysis of purified axin-containing protein complexes by liquid chromatography-tandem mass spectrometry revealed the presence of the ubiquitin protease USP34. Our results indicate that USP34 functions downstream of the β-catenin destruction complex to control the stability of axin and opposes its tankyrase-dependent ubiquitination. Reflecting on the requirement for tight control of axin homeostasis during Wnt signaling, interfering with USP34 function by RNA interference leads to the degradation of axin and to the inhibition of β-catenin-mediated transcription. Given the numerous human diseases exhibiting spurious Wnt pathway activation, the development of USP34 inhibitors may offer a novel therapeutic opportunity.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, M5S 3M2 Ontario, Canada.
authors.forename: Tony T H
authors.initials: TT
authors.lastname: Lui
authors.forename: Celine
authors.initials: C
authors.lastname: Lacroix
authors.forename: Syed M
authors.initials: SM
authors.lastname: Ahmed
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Goldenberg
authors.forename: Craig A
authors.initials: CA
authors.lastname: Leach
authors.forename: Avais M
authors.initials: AM
authors.lastname: Daulat
authors.forename: Stephane
authors.initials: S
authors.lastname: Angers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein; D015153:Blotting, Western; D002454:Cell Differentiation; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007739:L Cells; D051379:Mice; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D055550:Protein Stability; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D038501:Tankyrases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D038501:Tankyrases; D010450:Endopeptidases; C584673:USP34 protein, human; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex